Biomedical Engineering Reference
In-Depth Information
the activation gate cannot close until the inhibitor dissociates from the hERG
channel. Armstrong noted that the channel block due to small QA compounds,
such as tetraethylammonium, did not show interference with the deactivation rate,
suggesting that these compounds might be trapped in the hERG channel in the
closed state. A molecule can only be trapped only if it is small enough to fit into the
central cavity. If the molecule is charged, it cannot leave the central cavity through
the hydrophobic environment of the inner pore or through the membrane, hence the
block is irreversible until the channel reopens. Mitcheson et al. [
3
] used the potent
hERG blocker MK-499 and the hERG mutant D540K to test the trapping hypothe-
sis. This mutant of the hERG channel has the particular characteristic to open in
response to hyperpolarization. They observed that the channel reopening during the
hyperpolarization allowed the recovery from the block of MK499, as postulated by
the trapping hypothesis. Moreover, the observation that molecules with large size
such as MK499 (7
20
˚
) can be trapped, suggests that the hERG channel has a
central cavity bigger than the one of the Shaker K
þ
channel. The Shaker K
þ
channel is blocked by tetraethylammonium (6.9
˚
of diameter), but it cannot trap
MK499.
5.2.1 Case Studies: Propafenone Derivatives Trapping
Docking studies combined with alanine scanning of the amino acids facing the
central cavity were performed to investigate the molecular determinants of hERG
inhibition by propafenone, as well as the amino acids involved in the drug trapping
[
11
]. The mutagenesis data showed that propafenone's inhibition of hERG was
strongly dependent on the interactions between the compound and the amino acid
Phe656, while it was not affected by mutations of Tyr652, Thr623, Ser624, Val625,
Gly648 or Val659. The analysis of recovery from the propafenone block showed
that the compound was not released faster from the mutant channels T652A,
V625A, and S624A than from the wild-type channel. Only in the case of F656A
the recovery from the block is slightly faster. These results suggest that only the
mutation F656A slightly reduces the interaction of propafenone with the hERG
channel in the closed state. Their results also indicate that the mutagenesis data are
better rationalized with the docking poses obtained with the hERG channel in the
open state. Almost all of the top ranked poses form
-stacking interactions with two
Phe656 of adjacent subunits. The model of the hERG channel in the open state
suggests that the four Phe656 are highly accessible to the compound, whereas in the
closed-state model the space between the Phe656 units is reduced, making it
impossible for propafenone to form
p
-stacking interactions with Phe656. This
indicates that there are gating-induced changes in the position of Phe656 side
chains.
In a recent study, Thai et al. [
102
] used five propafenone derivatives to perform a
systematic analysis of use-dependency and recovery from the block of the hERG
channel. The pose of propafenone docked into the hERG channel in the closed state
predicts that the phenyl ring forms
p
p
-stacking interactions with Tyr652, that the
